This study is NOT currently recruiting participants.
Number
18-N-0083
Sponsoring Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Recruitment Detail
Type: No longer recruiting/follow-up only Gender: Male Min Age: 3 Years Max Age: 5 Years
Referral Letter Required
No
Population Exclusion(s)
Female
Keywords
Pediatric; Neuromuscular
Recruitment Keyword(s)
None
Condition(s)
Muscle Myopathies; Muscular Disease
Investigational Drug(s)
AT132
Investigational Device(s)
Intervention(s)
Genetic: AT132
Supporting Site
National Institute of Neurological Disorders and Stroke
X-Linked Myotubular Myopathy (XLMTM) is caused by a mutation in the MTM1 gene, which helps the body make the protein myotubularin. This causes severe muscle weakness in children. AT132 therapy gives the normal MTM1 gene to a child with XLMTM. This could help XLMTM symptoms.
Objective:
To see if AT132 is safe, increases myotubularin production, and helps symptoms in children with XLMTM.
Eligibility:
Boys under age 5 who:
Have XLMTM and a MTM1 mutation
Require mechanical breathing support
Design:
Participants will be screened with:
Physical exam
Blood, urine, and heart tests
Abdomen ultrasound
Medical history
Participants will join either the early treatment or delayed treatment group.
Participants will be admitted to the hospital. The next day they will get AT132 by IV infusion. They will stay in the hospital 1 or 2 nights. Two days after the infusion they will have the screening procedures, plus:
Performing simple tasks while being videotaped
Breathing tests: Participants will wear a facemask, breathing tube, or ventilator. Their airflow will be temporarily blocked.
Muscle biopsy. A small piece of muscle is taken from the participant s arm or leg under general anesthesia.
Wrist X-ray
Starting the day before their infusion, participants will take the drug prednisolone for 16 weeks.
Participants will have many visits over several years in this order:
Weekly for 2 months after the infusion
1 month later
Every 3 months for 1 year
Every 6 months for 5 years
Delayed treatment group participants will have visits 1 and 3 months after screening, then every 3 months for up to 1 year before receiving AT132.
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INCLUSION CRITERIA: 1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility. 2. Subject is male. 3. Subject is aged less than 5 years old at dosing. 4. Subject requires mechanical ventilatory support: --Part 1: Subject requires some mechanical ventilatory support (eg, ranging from 24 hours per day full time mechanical ventilation, to noninvasive support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) during sleeping hours). --Part 2: Subject requires invasive mechanical ventilatory support ranging from 20 to 24 hours per day at screening (confirmed by daytime polysomnographic study). 5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments. 6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cm H2O at screening. 7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when applicable). 8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study procedures. EXCLUSION CRITERIA: 1. Subject is participating in an interventional study designed to treat XLMTM. 2. Subject born < 35 weeks gestation who is still not term as per corrected age. 3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the age of 18 months may be retested in cases where antibodies may have been maternally acquired and titers may decline in the first months of life). 4. Subject had recent surgery (< 3 months before Day 1) or has planned surgery that may confound data collection during the first 48 weeks of the study. 5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the opinion of the Investigator. 6. Subject has a clinically significant underlying liver disease, defined as: -- >= Grade 3 aspartate aminotransferase (AST) (> 5.0 x upper limit of normal [ULN]; Common Terminology Criteria for Adverse Events [CTCAE] v. 4.03) -- >= Grade 3 alanine aminotransferase (ALT) (> 5.0 x ULN; CTCAE v. 4.03) -Hepatic peliosis or any other clinically significant structural abnormality detected by ultrasound 7. Subject is currently experiencing a clinically important respiratory infection or other active infection. 8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1. 9. Other than as required per protocol, subject has received immune-modulating agents within 3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 4 weeks before dosing. 10. Subject has a contraindication to prednisolone 11. Subject has a contraindication to study drug or ingredients 12. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair surgery/procedure in the 12 months following Day 1 (Part 2 including any subjects enrolled under protocol v8 and beyond). 13. Subject has contractures, scoliosis, or other medical condition that would limit the potential to achieve unassisted sitting, in the opinion of the Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond). 14. Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond). 15. Subject has a clinically important condition, including CTCAE v4.03 Grade >= 2 anemia (< 10 g/dL hemoglobin). 16. Subject has a contraindication to ursodiol (ursodeoxycholic acid). Note: If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132.
1. Subject has a diagnosis of XLMTM resulting from a genetically confirmed mutation in the MTM1 gene as assessed by a Sponsor-approved testing facility.
2. Subject is male.
3. Subject is aged less than 5 years old at dosing.
4. Subject requires mechanical ventilatory support:
--Part 1: Subject requires some mechanical ventilatory support (eg, ranging from 24 hours per day full time mechanical ventilation, to noninvasive support such as continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) during sleeping hours).
--Part 2: Subject requires invasive mechanical ventilatory support ranging from 20 to 24 hours per day at screening (confirmed by daytime polysomnographic study).
5. Subject requiring invasive mechanical ventilator support is fitted with or willing to be fitted with a cuffed tracheostomy tube for some respiratory assessments.
6. Subject has ventilator maximum positive end-expiratory pressure (PEEP) < 8 cm H2O at screening.
7. Signed informed consent by the parent(s) or legally authorized representative(s) (LAR) (when applicable).
8. Subject and parent(s)/LAR(s) are willing and able to comply with study visits and study procedures.
EXCLUSION CRITERIA:
1. Subject is participating in an interventional study designed to treat XLMTM.
2. Subject born < 35 weeks gestation who is still not term as per corrected age.
3. Subject tests positive for AAV8 neutralizing antibody with titers > 1:20 (subjects under the age of 18 months may be retested in cases where antibodies may have been maternally acquired and titers may decline in the first months of life).
4. Subject had recent surgery (< 3 months before Day 1) or has planned surgery that may confound data collection during the first 48 weeks of the study.
5. Subject has a clinically important condition or life-threatening disease, other than XLMTM, in the opinion of the Investigator.
6. Subject has a clinically significant underlying liver disease, defined as:
-- >= Grade 3 aspartate aminotransferase (AST) (> 5.0 x upper limit of normal [ULN]; Common Terminology Criteria for Adverse Events [CTCAE] v. 4.03)
-- >= Grade 3 alanine aminotransferase (ALT) (> 5.0 x ULN; CTCAE v. 4.03)
-Hepatic peliosis or any other clinically significant structural abnormality detected by ultrasound
7. Subject is currently experiencing a clinically important respiratory infection or other active infection.
8. Subject has received pyridostigmine or any medication to treat XLMTM within 3 months before Day 1.
9. Other than as required per protocol, subject has received immune-modulating agents within 3 months before Day 1 (use of inhaled corticosteroids to manage chronic respiratory conditions is allowed); use of other concomitant medications to manage chronic conditions must have been stable for at least 4 weeks before dosing.
10. Subject has a contraindication to prednisolone
11. Subject has a contraindication to study drug or ingredients
12. Subject has previous scoliosis repair surgery/procedure, or planned/expected scoliosis repair surgery/procedure in the 12 months following Day 1 (Part 2 including any subjects enrolled under protocol v8 and beyond).
13. Subject has contractures, scoliosis, or other medical condition that would limit the potential to achieve unassisted sitting, in the opinion of the Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond).
14. Subject is able to sit without assistance for at least 30 seconds at screening, in the opinion of the Investigator (Part 2 including any subjects enrolled under protocol v8 and beyond).
15. Subject has a clinically important condition, including CTCAE v4.03 Grade >= 2 anemia (< 10 g/dL hemoglobin).
16. Subject has a contraindication to ursodiol (ursodeoxycholic acid).
Note: If a subject is a delayed-treatment control, this inclusion/exclusion criterion must be met before receiving AT132.
Principal Investigator
Referral Contact
For more information: